Project Summary This study will be the first of its kind globally, comparing [18F]RO-948, a radiopharmaceutical developed from an extensive series of well-characterized tau radioligands by Wong/Kuwabara MPIs with an increasingly used next-generation radiopharmaceutical, [18F]MK-6240. The primary aim of which would be to identify a more optimal radioligand for tau imaging of tauopathy in Alzheimer?s disease (AD) through direct comparisons of these two potential candidates, and demonstration of their lack of off target binding which is suffered by commonly used [18F]AV1451. These next generation radiopharmaceuticals ([18F]MK-6240 and [18F]RO-948) both have a different chemical structure and somewhat different pharmacologic profile; therefore, we anticipate definitive differences in distribution volume ratios, standardized uptake ratios at optimal delayed imaging times and off-target binding. Ten subjects with Alzheimer?s disease, diagnosed by Alzheimer?s Disease Research Center (ADRC) and/or DSM criteria will be studied with both radiopharmaceuticals. We hypothesize these tracers to show similarly good results in the kinetic evaluations, specifically that [18F]RO-948 shows lower binding than [18F]MK-6240 in the cerebellum and white matter regions and is associated with better discrimination of AD subjects from healthy controls. Additionally we will examine these next-generation tracers in terms of off-target binding potential within the basal ganglia, thalamus, and choroid plexus; hypothesizing lower binding than that of the currently regarded [18F]AV1451. If supported, these hypotheses will provide a rationale for selecting [18F]RO-948 or [18F]MK-6240 compared to [18F]AV1451 for studying tau accumulation in AD. It is critical to demonstrate which radioligand is better for discrimination of AD from OC in the proposed same-subject design, as well as, examine potential for off-target binding. This innovative comparison of the three radioligands in head-to-head interrogation will yield critical information for selection of radioligands for research in the field of neuroimaging of tau.